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Exploring inflammatory disease drug effects on neutrophil function.

ABSTRACT: Neutrophils are critical inflammatory cells; thus, it is important to characterize the effects of drugs on neutrophil function in the context of inflammatory diseases. Herein, chemically guided neutrophil migration, known as chemotaxis, is studied in the context of drug treatment at the single cell level using a microfluidic platform, complemented by cell viability assays and calcium imaging. Three representative drugs known to inhibit surface receptor expression, signaling enzyme activity, and the elevation of intracellular Ca(2+) levels, each playing a significant role in neutrophil chemotactic pathways, are used to examine the in vitro drug effects on cellular behaviors. The microfluidic device establishes a stable concentration gradient of chemokines across a cell culture chamber so that neutrophil migration can be monitored under various drug-exposure conditions. Different time- and concentration-dependent regulatory effects were observed by comparing the motility, polarization, and effectiveness of neutrophil chemotaxis in response to the three drugs. Viability assays revealed distinct drug capabilities in reducing neutrophil viability while calcium imaging clarified the role of Ca(2+) in the neutrophil chemotaxis. This study provides mechanistic insight into the drug effects on neutrophil function, facilitating comparison of current and potential pharmaceutical approaches.

SUBMITTER: Wu X

PROVIDER: S-EPMC4119782 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Exploring inflammatory disease drug effects on neutrophil function.

Wu Xiaojie X Kim Donghyuk D Young Ashlyn T AT Haynes Christy L CL

The Analyst 20140801 16

Neutrophils are critical inflammatory cells; thus, it is important to characterize the effects of drugs on neutrophil function in the context of inflammatory diseases. Herein, chemically guided neutrophil migration, known as chemotaxis, is studied in the context of drug treatment at the single cell level using a microfluidic platform, complemented by cell viability assays and calcium imaging. Three representative drugs known to inhibit surface receptor expression, signaling enzyme activity, and ...[more]

PMID: 24946254

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Project description:BACKGROUND:Studies suggest a role of the innate immune system, including the activity of neutrophils, in neurodegeneration related to Alzheimer's disease (AD), but prospective cognitive data remain lacking in humans. We aimed to investigate the predictive relationship between neutrophil-associated inflammatory proteins in peripheral blood and changes in memory and executive function over 1?year in patients with AD. METHODS:Participants with AD were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Neutrophil gelatinase-associated lipocalin (NGAL), myeloperoxidase (MPO), interleukin-8 (IL-8), macrophage inflammatory protein-1 beta (MIP-1?), and tumor necrosis factor (TNF) were assayed by luminex immunofluorescence multiplex assay at baseline. Confirmatory factor analysis was used to test an underlying neutrophil associated plasma inflammatory factor. Composite z-scores for memory and executive function were generated from multiple tests at baseline and at 1?year. A multiple linear regression model was used to investigate the association of the baseline inflammatory factor with changes in memory and executive function over 1?year. RESULTS:Among AD patients (n?=?109, age?=?74.8?±?8.1, 42% women, Mini Mental State Examination [MMSE]?=?23.6?±?1.9), the neutrophil-related inflammatory proteins NGAL (??=?0.595, p?<?.001), MPO (??=?0.575, p?<?.001), IL-8 (??=?0.525, p?<?.001), MIP-1? (??=?0.411, p?=?.008), and TNF (??=?0.475, p?<?.001) were found to inform an underlying factor. Over 1?year, this inflammatory factor predicted a decline in executive function (??=?-?0.152, p?=?0.015) but not memory (??=?0.030, p?=?0.577) in models controlling for demographics, brain atrophy, white matter hyperintensities, the ApoE ?4 allele, concomitant medications, and baseline cognitive performance. CONCLUSIONS:An inflammatory factor constructed from five neutrophil-related markers in peripheral blood predicted a decline in executive function over 1?year in people with mild AD.

Dataset Information

Exploring inflammatory disease drug effects on neutrophil function.

Publications

Exploring inflammatory disease drug effects on neutrophil function.

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